Beverage containing alpha-ketoglutaric acid and method of making

ABSTRACT

The present invention is related to an energy supply composition particularly suitable for use before, during and after physical exertion. The composition is a beverage, or a dry composition therefore, useful as an energy source in situations which demand a large and rapid energy supply to a healthy mammal including man. The beverage comprises an effective amount of alpha-ketoglutaric acid or a water-soluble innocuous salt thereof together with a nutritionally acceptable water-soluble carrier.

TECHNICAL FIELD

The present invention is related to an energy supply compositionparticularly suitable for use before, during and after physicalexertion.

The object of the invention is to facilitate extended physical exertionby providing energy that is efficiently utilized in mammals. A furtherobject of the invention is to facilitate the accretion of muscle tissueas a result of physical training by sustaining an adequate energy statusand permitting rapid build-up of the body's stored energy levels uponrest. A further object is to reduce the loss of water from the bodyduring physical exertion by retaining a high rate of water absorption inthe gastrointestinal tract from an energy rich beverage.

BACKGROUND OF THE INVENTION

Individuals undergoing significant physical exertion, whether forathletic or other purposes increase their nutritional needssubstantially in order to maintain the body's energy storage and todevelop its muscular capacity. If physical training is not accompaniedby a proportional increase in nutritional intake, the muscle glycogendepot is not replenished unless proteins, principally from musclesources, is broken down into constituent amino acids, chiefly alanineand glutamine, to be used as required energy or converted to glucose.

In the last decades, so called sports beverages have enjoyed anincreased use by athletes and others doing exercise. Such beverages havelargely been based on sugars, salt, minerals and proteins and fragmentsthereof. For example, in Dialog Abstract No 02331774 (World Food & DrinkReport, Oct. 19, 1989) a sports drink named GatorPro is describedincluding water, glucose, soy protein isolate and soy oil. Variousattempts have been made to provide a beverage, based on a soundscientific concept, for athletes and other healthy individuals with ahigh energy demand, e.g. certain convalescents. However, the demand forimproved beverages is still great. By a healthy individual in thecontext of this invention is intended a human and, as applicable,another mammal individual who is not subject to neither in-patient norout-patient care for conditions relevant herein by a hospital or amedical or veterinary practitioner. Thus the term excludes patientsrequiring parenteral, or equivalent enteral, supply of the entire or avery large proportion of the energy, electrolyte, fat or amino aciddemand of such patient. On the other hand, the term includes thoseathletes and convalescents just mentioned and other individuals in asimilar physical state, although they may have deficiencies or surplusin their body tissues and liquids as compared to an avarage non-diseasedand fit individual.

Normally, physical exertion is accompanied by an increase in foodintake, and the energy requirements of the intestine, i.e. the smallintestine, for digestion are thus also increased in order to provideactive transport of substances into the blood stream and to sustain theturnover in epithelial cells that makes up the luminal lining of theintestine. In situations of substantially increased food intake, theintestinal absorption efficiency (i.e. the supply of energy) may bedecreased. Thus, an increased demand for energy must be accompanied by aproportionally even higher food intake to avoid metabolic imbalance.

In contrast to some other tissues, the small intestine's primary energysource is the amino acid glutamine. During a meal, glutamine is mainlyobtained directly from the food. Between meals, however, glutamine istransported from the muscles, where it is derived from proteinbreakdown, to the intestine.

In the healthy individual, glutamine is classified as a non-essentialnutrient, that is, the body provides enough glutamine to satisfy themetabolic demand for said amino acid. After physical trauma, whetheraccidental or intentional (e.g. surgery), some non-essential nutrientsseem to become semi-essential in order to preserve physical functionssuch as nitrogen balance and immune function (Kirk S J and Barbul A,JPEN 14, 226-229, 1990; Ziegler T R et al Clin Nutr 12(1), 82-90, 1993).A person in nitrogen balance ingests as much nitrogen (primarily in theform of protein) as is lost in feces, urine and by transpiration. Aperson in positive nitrogen balance ingests more nitrogen than is lost.External glutamine supply decreases the loss of muscle protein afterphysical trauma and supports the intestinal barrier against infectionscaused by microorganisms of the gastrointestinal tract. Due to thechemical instability of glutamine, which cyclesizes to a toxic compoundduring storage, only a few nutritional products are supplemented withthis amino acid.

The main energy depots of the body comprise large molecules synthesizedfrom monomers of glucose, amino acids or fatty acids and glycerol. Theformation of these large molecules makes it possible to store a largeamount of energy without changing osmotic pressure beyond acceptablelimits within the mammal or disturbing substrate and product basedregulation of metabolism. On the other hand, the energy depots of themuscle admit a fairly slow inter organ transport of energy. See the Coricycle, FIG. 1. The Cori cycle is a pathway describing the exchange offuel molecules and building blocks for biosynthesis, between muscle andliver. The evolution of energy transport cycles and depots is welladjusted to a natural situation of intermittent nutrient intake.

A drawback of the natural energy depot system is the rather inefficientreplenishment of the rapid cellular energy sources such as ATP andcreatine phosphate from glucose, and the accumulation of metabolic wasteproducts, such as lactic acid. The accumulation of lactic acid,resulting in an obvious oxygen debt, is a well known limiting factor forphysical performance. In MEDLINE/93009547 (Clin Sci September 1992;83(3):367-74) Harris et al show that creatine given as a supplement tonormal subjects resulted in an increase in the total creatine content inmuscle. However, a larger creatine content does not directly increasethe stored energy, but increases the ability to store energy.

The citric acid cycle is the final common pathway for the oxidation offuel molecules. It also serves as a source of building blocks forbiosynthesis. See FIG. 2. Clinical settings on humans and animal studieshave suggested that the keto acid α-ketoglutaric acid, a glutaminerelated metabolite of the citric acid cycle, has an impact similar toglutamine, on the muscle protein balance during stress and medicaltreatment (Patent SE 462 463, U.S. Pat. No. 5,183,674; Wernerman J. etal, Lancet 335, 701-703, 1990). Intravenous administration ofα-ketoglutaric acid, but not glutamine, improves the energy status ofthe muscle in critically ill patients (Gamrin L, ESPEN 1993, abstract O48), indicating a metabolic discrepancy between the two nutrients asregards impact on energy status.

In the healthy individual, glucose and fatty acids are the predominantenergy substrates for the muscle. During physical exertion glucose isthe most rapidly mobilized energy source in skeletal muscle. However,the normal storage capacity of glucose is limited and, more importantly,the muscular work in so-called "fast and medium fast fibres" is notbalanced by a corresponding increase in glucose uptake from the bloodstream, and such loss of balance causes reduction in the glucose(glycogen) reserve. As the glycogen reserve is diminished, there is anincreased utilization of fatty acids in the muscle. The change fromglycogen (glucose) to a fatty acid derived energy production isconcomitant with a decreased muscular efficiency.

Although the muscle glycogen depot is the predominant carbohydratesource in the working muscle, there is some transport of blood glucoseinto the muscle. Closer to the point of exhaustion, blood derivedglucose becomes increasingly important to the muscle as a carbohydratesource. Nevertheless, the fall in plasma insulin during exercisecounteracts the transport of glucose into the muscle, presumably topreserve the blood glucose at a concentration adequate to ensure a wellfunctioning central nervous system.

Pyruvate in combination with dihydroxyacetone increases the muscleuptake of glucose both at rest and during exertion (Stanko R T et al, JAppl Physiol 69(5), 1651-1656, 1990) resulting in an improved legexercise endurance. In practice, the combination of pyruvate anddihydroxyacetone is not satisfactory due to poor chemical stability.

A typical beverage designed to support energy status during physicalexertion is an isotonic aqueous solution which includes traditional foodingredients such as glucose, fructose and galactose and salts. Becauseof a limited transport of these sugars into the muscle during physicalexertion, they are not optimally utilized as energy substrates. Further,even small amounts of sugar tend to delay the water absorption due todecreased water passage through the pylorus. Even a limited loss ofwater, corresponding to four to five percent of the body weight, resultsin a marked decrease in muscular work and a concomitant loss of bodyprotein.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference is now made to the drawings accompanying the inventionwherein:

FIG. 1 is a schematic diagram of the Cori cycle; and

FIG. 2 is a schematic diagram of the citric acid cycle.

DESCRIPTION OF THE INVENTION

The present invention provides a beverage, or a dry compositiontherefor, useful as an energy source in situations with demand of largeand rapid energy supply to a healthy mammal including man, comprising aneffective amount of α-ketoglutaric acid or a water-soluble innocuoussalt thereof together with a nutritionally acceptable water-solublecarrier.

According to another aspect, the invention is related to a method oflarge and rapid energy supply to a healthy mammal including man,comprising providing to said animal, a beverage, or a dry compositiontherefor, comprising an effective amount of α-ketoglutaric acid or awater-soluble innocuous salt thereof together with a nutritionallyacceptable water-soluble carrier.

According to a further aspect, the invention is related to the use of aneffective amount of α-ketoglutaric acid or a water-soluble innocuoussalt thereof together with an acceptable water-soluble carrier, forpreparation of a beverage, or a dry composition therefor, for use as anenergy source in situations with demand of large and rapid energy supplyto a healthy mammal including man.

In contrast to sugars such as glucose, the beverage of the inventionprovides energy with only a minimal increase of water retention in thestomach and will thus counteract the loss of water from the body duringphysical exertion more efficiently than conventional sugar containingbeverages. The enhanced water balance minimizes the loss of body proteinduring exercise.

Preferred embodiments of the invention will be evident from thefollowing descriptions and claims.

The nutritionally acceptable water-soluble carrier preferably includesone or more of the components: minerals, vitamins, carbohydrates, fatand protein, and is in dry form if the beverage is provided as anextract for dilution. If the beverage is provided ready for consumptionit further comprises water. From the stated purpose with the beverage ofthe invention it will be apparent that the beverage is preferably notintended to fulfil to any substantial degree the requirements of saidindividual of several free, in particular several essential free, aminoacids. The final beverage may have controlled tonicity and acidity, e.g.as a buffered solution. Among further ingredients may be mentioned malicacid, which enhances the rate of energy generating oxidation ofα-ketoglutaric acid. Accordingly, the combination of α-ketoglutaric acidand malic acid is one preferred embodiment of the invention. Preferably,the ratio of alpha-ketoglutaric acid to malic acid is 1:0.5 to 1:1.5.Also, preferably, the amount of sugar(s) is below 350 millimoles ofmonosaccharides per liter.

Two particularly preferred beverages of the invention are as follows:

    ______________________________________                                        Beverage for increasing endurance                                                                   Preferred range of                                      Ingredient            content per 100 ml                                      ______________________________________                                        α-ketoglutaric acid                                                                           0.5-2 g                                                 Malic acid*           0.3-3 g                                                 Glucose or a di- or polysaccharide                                                                  1-8 g                                                   containing glucose                                                            Fructose*             0.5-1.5 g                                               Sodium, Potassium and Calcium                                                                       0.1-0.5 g                                               Aroma, such as citric acid                                                                          0.5-2.5 g                                               and/or lime concentrate                                                       Water                                                                         Energy                10-50 kcal                                              α-ketoglutaric acid                                                                           1.0-1.5 g                                               Malic acid*           0.3-3 g                                                 Glucose or a di- or polysaccharide                                                                  2-6 g                                                   containing glucose*                                                           Fructose*             0.5-1.5 g                                               Sodium, Potassium and Calcium                                                                       0.1-0.5 g                                               Aroma, such as citric acid                                                                          0.5-2.5 g                                               and/or lime concentrate                                                       Water                                                                         Energy                10-50 kcal                                              ______________________________________                                         *optional                                                                

Beverage for Energy Replenishment

In order to provide a nutritiously more complete replenishment afterphysical exertion the following ingredients may be added to the formulaof above described beverages:

    ______________________________________                                                               Preferred range of                                     Ingredient             content per 100 ml                                     ______________________________________                                        Lipids and fatty acids*                                                                              0.1-1.0 g                                              Water-soluble protein, e.g. whey protein                                                             1-5 g                                                  Essential minerals according to WHO**                                                                0.1-0.3 g                                              Vitamins according to WHO**                                                                          0.01-0.1 g                                             Energy                 5-25 kcal                                              ______________________________________                                         *optional                                                                     **Handbook on Human Nutritional Requirements, Geneva, WHO, Monogr. Serial     No 61 (1974), and Nutr. Metab. 21, p 210 (1977).                         

In contrast to other keto acids α-ketoglutaric acid is stable, and hencesuitable for use in beverages. The pH of the beverages is preferably inthe range of about 2-5, an in particular about 2-4, to prevent bacterialand fungal growth. Due to the stability of α-ketoglutaric acid theproduction of a sterilised beverage at a pH of about 6-8 is alsopossible.

The beverage of the present invention provides energy according to theprinciple of rapid energy recruitment within the organelles of themammalian cell. An organelle is a sub-cellular compartment representingspecialized metabolic function, such as the mitochondria were theformation of energy by oxidative reaction in the citric acid cycle takesplace. (See citric acid cycle, FIG. 2). The main energy substrate of thesaid beverage, α-ketoglutaric acid, is rapidly converted to energy orother metabolites, such as glucose, and a minimum of metabolic wasteproducts. Further, α-ketoglutaric acid stimulates the transport ofglucose from the blood into the muscle. The invention will therebyenhance the performance of muscle fibres and save or replenish theindigenous energy depot resulting in an enhanced physical and mentalendurance. Also, α-ketoglutaric acid, a constituent in thegluconeogenesis, increases the glycogen deposition when administeredbefore exertion, leading to improved exercise endurance.

α-ketoglutaric acid is formed in each cell that is active in terms ofoxidative metabolism and/or amino acid deamination reactions, and istherefore not considered as an essential nutrient. The cells of theintestinal mucosa utilize α-ketoglutaric acid, derived from glutamine,as an energy substrate. This reaction has not, until now, beenconsidered to be limiting for an optimal intestinal function in healthyindividuals. Athletes consuming two to four times as much calories asthe untrained person, have not been thoroughly studied from such aspect.A further advantage is provided by the invention on the intestinalfunction exemplified by a sustained absorption efficiency during periodsof large food intake, which permits a rapid build-up of the body'sstored energy levels upon rest.

Taken together, the improved muscle energy and water supply duringphysical exertion and the sustained intestinal absorption during periodsof large food intake, make the invention facilitate the accretion ofmuscle tissue as a result of physical training.

The following examples and tests are provided by way of illustration andnot by way of limitation.

EXAMPLES OF PREFERRED BEVERAGES Example 1

    ______________________________________                                        Ingredient         Content per 100 ml                                         ______________________________________                                        α-ketoglutaric acid                                                                        1.2 g                                                      Glucose or a di- or polysaccharide                                                               2.5 g                                                      of glucose                                                                    Fructose           1.0 g                                                      Sodium, Potassium and Calcium                                                                    0.3 g                                                      Citric acid and/or lime concentrate                                                              1.5 g                                                      Water                                                                         Energy             19 kcal                                                    ______________________________________                                    

Example 2

    ______________________________________                                        Ingredient           Content per 100 ml                                       ______________________________________                                        α-ketoglutaric acid                                                                          1.5 g                                                    Glucose or a di- or polysaccharide                                                                 4.0 g                                                    of glucose                                                                    Fructose             1.0 g                                                    Lipids and fatty acids                                                                             0.1 g                                                    Water-soluble protein                                                                              3.0 g                                                    Sodium, Potassium and Calcium                                                                      0.3 g                                                    Essential minerals according to WHO*                                                               0.2 g                                                    Vitamins according to WHO*                                                                         0.05 g                                                   Citric acid and/or lime concentrate                                                                1.5 g                                                    Water                                                                         Energy               39 kcal                                                  ______________________________________                                         *Handbook on Human Nutritional Requirements, Geneva, WHO, Monogr. Serial      No 61 (1974), and Nutr. Metab. 21, p 210 (1977).                         

STABILITY TEST

Two beverages, A and B, were prepared according to the compositions inexample 1 and 2, respectively. Beverage A and B were each divided intofour samples and treated as follows:

Sample one: Stored at room temperature for 24 hours.

Sample two: Autoclaved at 120° C. for 25 minutes.

Sample three: Sterilized by heating to 140° C. for 5 seconds (ultra hightemperature sterilization, UHT)

Sample four: Sterilized according to sample 3 and then stored at roomtemperature for 6 months.

The samples were then analyzed for the content of α-ketoglutaric acid,by glutamate dehydrogenase specific NADH oxidation.

RESULTS

After treatment of the samples one, two and three, more than 95 percentof the α-ketoglutaric acid added was recovered from both beverage A andB. When stored for six months (sample four) the content ofα-ketoglutaric acid in the two beverages was more than 90 percent of theadded amount. The biological value of other ingredients of the beverageswere not negatively affected by the presence of α-ketoglutaric acid.

PHYSICAL TESTS

Physical Exertion Program:

Running 6 kilometers three times a week at a speed corresponding to60-70% of maximal capacity.

50-60 sit-ups and 30-40 arm push-ups four times a week.

Physical Test 1

Study Group

Six healthy men, who on a regular base, practised physical exerciseaccording to the training program above during at least one year priorthe onset of the study.

The study were divided into two periods:

I. The test persons practised physical exercise, as described, for onemonth. During this month they consumed three times 200 ml per day of anenergy rich conventional beverage for sportsmen, containing salts and7.5 g of glucose per 100 ml.

II. The test persons continued their physical exercise according to theprotocol for a second month. At the start of this month, they changedfrom a conventional beverage to consumption of three times 200 ml perday of a beverage according to the present invention (see Example 1)

RESULTS

During study period (I), when provided the conventional beverage, thehealthy men did not improve their physical performance. A change to thebeverage according to the invention (study period II), was concomitantwith an increased physical performance corresponding 10 to 20 percent ofaverage running speed and number of situps and push-ups beforeexhaustion.

Further, when consuming a beverage according to the invention, theoxygen debt was less pronounced during the day to day intensive shortterm physical exertion.

As the conventional sugar containing beverage was consumed, close to andduring physical exertion, a heavy stomach revealed a slow absorption ofthe liquid. In contrast, the beverage composed according to the presentinvention was effectively absorbed when used closed to and duringexertion.

Physical Test 2

Six healthy men performing a weekly physical exercise as described inPhysical Test 1 were provided with a beverage according to the presentinvention during a period of six months. The beverage was composedaccording to Example 1, except from a varying content of α-ketoglutaricacid between 0.01 and 3.5 gram per 100 ml and malic acid in relationthereto. The different beverages were kept isocaloric by compensatingthe varying content of organic acids with a proportional amount ofglucose.

RESULTS

The test persons reported an enhanced endurance during physical exertionwhen consuming a beverage including 0.1 to 2.5 g of α-ketoglutaric acidper 100 ml. Immediately after exercise, the consumption of a beveragecontaining a combination of α-ketoglutaric acid and malic acid, resultedin a significantly faster energy boost as compared to a beveragecontaining α-ketoglutaric acid alone.

Physical Test 3

Study Group

Six well trained long distance runners joined the study during atraining period according to the Physical Exertion Program above. Theathletes were provided a beverage of the invention according to Example2. During a study period of one month, they consumed 600 to 800 ml perday of the beverage.

RESULTS

The athletes recorded an increased training tolerance the day afterheavy exercise, as a retained endurance. The onset of muscle fatigueduring physical exercise was postponed and correlated to a decreasedaccumulation of lactic acid. Further, the athletes interpreted part ofthe impact of the beverage on physical performance, as a rapid build-upof the body's stored energy levels upon rest. The increased trainingtolerance in combination with a high level of stored energy minimize thecombustion of amino acids and thus facilitates, accretion of muscleprotein and development of muscle performance.

I claim:
 1. A beverage, or a dry composition therefor, providing anenergy source in situations with demand of large and rapid energy supplyto a healthy mammal comprising 0.1 to 2.5 percent of the wet weight ofα-ketoglutaric acid or a water-soluble innocuous salt thereof togetherwith a nutritionally acceptable water-soluble carrier.
 2. A beverage, ora dry composition therefor, according to claim 1, wherein α-ketoglutaricacid is combined with malic acid.
 3. A beverage according to claim 2,wherein the ratio α-ketoglutaric acid:malic acid is 1:0.5 to 1:1.5.
 4. Abeverage, or a dry composition therefor, according to claim 1,comprising an acid and heat stable whey protein concentrate making up a1 to 20 percent visually clear water solution.
 5. A beverage accordingto claim 1 wherein the nutritionally acceptable water-soluble carrierincludes at least one of the components: water, minerals, vitamins,organic acids, carbohydrates, fat and protein in a water-soluble form.6. A beverage according to claim 1, wherein the beverage furtherincludes sugar(s) in amounts below 350 millimoles of monosaccharides perliter.
 7. A method of large and rapid energy supply to a healthy mammal,comprising providing to said animal, a beverage, or a dry compositiontherefor, comprising 0.1 to 2.5 percent of the wet weight ofα-ketoglutaric acid or a water-soluble innocuous salt thereof togetherwith a nutritionally acceptable water-soluble carrier.